6-methyl steroids and process for producing same



United States Patent 3,170,935 -METHYL STERGIDS AND PROCESS FOR PRGDUCING SAME Winifred dune Adams, Bernard Eiiis, Vladimir Petrow, and Isobel Ann Smart-Webb, ail of London, England, assignors to The British Drug Houses Limited, London, Engiand, a British company No Drawing. Filed Get. 6, 1959, Ser. No. 844,648 Claims priority, application Great Britain, June 9, 1955, 16,645/'5; June 20, 1955, 17,799/55; June 22, 1955, 18,118/55 8 Claims. (Cl. 266-3975) This invention is for improvements in or relating to organic compounds and has particular reference to the preparation of new 65-methyl-3-oxo-A -steroids of the androstane and pregnane series. This application is a continuation-in-part of our copending applications Serial No. 599,119 filed June 8, 1956, now abandoned, and Serial No. 592,243 filed June 19, 1956.

It is an object of the invention to provide new compounds of the androstane and pregnane series which are of value on account of their biological properties (e.g. anabolic and androgenic activity or progestational properties), or as intermediates in the preparation of compounds with useful biological properties, for example, in the preparation of 6a-methyl-3-oxo-A steroids of the androstane and pregnane series which are valuable as anabolic and progestational agents.

The invention provides new 6B-methyl-3-oxo-A steroids of the androstane and pregnane series and in particular the compounds 17B-hydroxy-6B-methylandrost- 4-en-3-one (6fi-memyltestosterone), 6f3-methylandrost-4- ene-3z17-dione, 17a ethinyl 17B hydroxy Gfi-methylandrost-4-en-3-one (6B-methyl ethisterone), and 6,8 methylpregn-4-ene-3 :ZO-dione (6fi-methyl progesterone). These compounds, as disclosed in our copending application Serial No. 592,243, are readily isomerized to the corresponding 6a-met'ny1 epimers by alkaline or acidic reagents.

According to the present invention there is provided a method for the preparation of 6,8-methyl-3-oxo-A steroids of the androstane and pregnane series having the general formula which method comprises oxidising a 3,8-hydroxy-6/3- methyl-A -steroid of the androstane and pregnane series having the general formula Me (II) androstane and pregnane series (Formula I above) may be prepared by oxidising a 3fiz5u-dihydroxy-6fi-methyl steroid of the androstane and pregnane series of the general Formula III (below) H0 Me (IV) and dehydrating the 5ot-hydroxy-6fl-methyl-3-oxo derivative. The oxidising agent is preferably chromium tri oxide in acetic acid or pyridine or potassium chromate in aqueous acetic acid but other oxidants such for example as N-bromoacetamide may also be employed. The dehydrating agent may be thionyl chloride in pyridine at 0 C. but other dehydrating agents may be used. For example, the Oppenauer reagent (i.e. aluminum isopropoxide or tert.-butoxide in toluene and *cyclohexanone) may be employed to perform the oxidation reaction and the dehydration reaction in one operation. Hydroxyl groups (other than those at C and C and oxo-groups (other than those at C present in the intermediates leading to compound (I) which may undergo change during the oxidation and dehydration reactions will naturally be protected in suitable manner by methods well known to those skilled in the art and subsequently regenerated. The choice of procedure for the preparation of any particular 6B-methyl-3-oxo-A -steroid described herein has been found to depend upon the nature of the substituents borne by the immediate precursor.

Following is a description by Way of example of methods of carrying the invention into efiect:

EXAMPLE 1 6 B-methyltestosterone (a) 6,8-methy1androst-4-en-3B:17/3-diol (660 mg.) in dry benzene ml.) was shaken for three days'with freshly prepared manganese dioxide (4 g.). Thereafter, inorganic material was removed by filtration and washed several times with Warm benzene. The combined filtrate and washings Was washed with dilute hydrochloric acid, then with dilute aqueous sodium carbonate and finally with water. The solid residue obtained after drying and removal of the solvent was crystallised from acetone/hexane to give 17,6-hydroxy-6fi-methylandrost-4-en 3-one (6fl-methyltestosterone) in needles, M.P. 212 to 214 C., [a] "+57 (c., 0.837 in chloroform), i 241 In (4.19) in isopropanol.

(b) 6,8-methylandrost-4-en-3fi:17,8-diol (200 mg.) in dry isopropanol (5 ml.) and dry acetone (2 ml.) was treated with aluminium tert.-but0xide (1 g.) for 18 hours at room temperature. After dilution with dilute hydrochloric acid, the product was isolated with ether and purified from acetone/hexane. 6,8 methyltestosterone was obtained in needles, MP. 212 to 214 C., not

depressed in admixture with a specimen prepared by method (a) above.

GB-methyltestosterone (100 mg.) in methanol (36 ml.) was heated with potassium hydroxide (400 mg.) under reflux in a stream of nitrogen for 20 hours. After dilution with water and acidification with acetic acid, the product was extracted with ether. Removal of the ether left a crystalline residue which was purified with ethanol to give 6a-methyltestosterone, M.P. 154 to 155 C., [u] +90 (c., 0.34 in chloroform), )t 24lmu (4.2) in isopropanol.

EXAMPLE 2 6B-methylandrostl-erte-3:17-di0ne (a) 6 8 methylandrostane-3flz5az17,8-triol (prepared by the method of Ushakov and Kosheleva, J. Gen. Chem. U.S.S.R. 1940, 10, 213) (2.57 g., crude) was dissolved in acetic acid (100 ml.) (distilled over chromium trioxide) and cooled .to l C. Chromium trioxide (2.5 g.) in acetic acid (40 ml.) and water (10 ml.) was added dropwise over minutes, keeping the temperature at 10 to 15 C. The mixture was stirred at room temperature for a further 2% hours. Methanol was added, and much of the acetic acid was removed in vacuo. After isolating with ethyl acetate, 5a hydroxy 6,8- methylandrostane-S:17-dione, M.P. 226 to 227 C., [a] +68 (c., 0.324 in chloroform) was obtained as needles from acetone/hexane.

5 a-hydroxy-6fl-methylandrostane-3 l7-dione (200 mg.) in dry pyridine (3 ml.) was cooled to 0 C. Purified thionyl chloride (0.12 ml.) was added dropwise and the mixture kept at 0 C. for five minutes. On treating with water a precipitate was formed, which was filtered off and dried. Crystallisation from acetone/hexane gave 6fi-methylandrost-4-en-3:17-dione in needles, M.P. 212 to 213 C., [a] +141 (c., 0.356 in chloroform), A 240mp (4.2) in isopropanol.

(b) 615' methylandrostane 3 3:5a:17,8 triol (820 mg.) in toluene (8 ml.) and cyclohexanone (10 ml.)

was treated with aluminium tert.-butoXide (1 g.) and the mixture heated under reflux for 2 hours. After washing with aqueous Rochelle salt, the solvents were removed by steam-distillation, and the oily product in pyridine (8 ml.) added at 5 C., to chromium trioxide (800 mg.) in pyridine (8 ml.). The reaction mixture was left overnight at room temperature and the product isolated with benzene. Chromatography on alumina (25 g.) gave 6,8-methylandro'st-4-en-3:17-dione, identical with a sample prepared by method (a). ylandrost-4-en-3z17-dione (25 mg.) in methanol (9 ml.) was refluxed for 19 hours under nitrogen with potassium hydroxide (100 mg.) in water (1 ml.). The mixture was neutralized with acetic acid, and the product isolated with ether. tained, crystallizing from acetone/hexane in needles, M.P. 162 C.

EXAMPLE 3 ofi-methylethisterone A solution of 170: ethinyl-6fi-methylandrostane- 3flz5azl7fi-triol (4.5 g.) in toluene (200 ml.) and cyclohexanone (40 ml.) was distilled until ml. of distillate had collected. After the addition of aluminium isopropoxide (2.5 g.) in toluene (10 ml.) the mixture was refluxed for 1 hour, cooled, washed with dilute mineral acid, and the solvents removed by steam-distillation. The crystalline product was purified .from aqueous ethanol to give fine needles of 17a-ethinyl-l7p-hydroxy-6pmethylandrost-4-en-3-one (6/8-methylethisterone), M.P. 223 to 225 C., [A -22 (c., 0.80 in chloroform), a 24lm (4.25) in isopropanol. 6B-methylethisterone (1.5 g.) in aqueous ethanol ml. of containing 6a-methylandrost-4-en-3:17-dione was obpotassium hydroxide (1.5 g.) was heated under reflux for 5 hours. The mixture was diluted with water, the product extracted with ether, and the washed and dried extract concentrated to low volume. The crystalline deposit Was purified from aqueous methanol to give 170;- ethinyl 17B hydroxy 6a methylandrost 4 en 3- one (6a-methylethisterone), prisms, M.P. 195 to 197 C., [u] +34.5 (c., 0.87 in chloroform).

EXAMPLE 4 6 fl-methyl progesterone (a) 6,8-met-hylallopregnane-3fi:5a:20(a+ 8)triol (5 g.) in acetic acid (50 ml.) was treated with chromium trioxide (3 g.) in 85% acetic acid ml.) and the mixture kept overnight at room temperature. Addition of water gave a solid which was collected and purified from ethanol. 50: hydroxy 6B methylallopregnane- 3:20-dione formed prisms, M.P. 255 to 256 C., [a] +64.5 (c., 0.49 in chloroform).

Thionyl chloride (1.2 ml.) was added dropwise to a solution of 5a hydroxy 6/8 methylallopregnane- 3:20-dione (2 g.) in dry pyridine (35 ml.) maintained at 0 C. After a further 10 minutes at this temperature the mixture was poured into ice-water and the product isolated with ether. Crystallised from aqueous methanol, 6B methylpregn 4 ene 3 :20 dione (MB-methylprogesterone) formed needles, M.P. 169 to 171 C., [a] +l4-1 (c., 0.954 in chloroform), k 242m (4.27) in ethanol.

(b) A solution of 6,8-methylallopregnane-3fi:5az20 (m+6)triols (1.5 g.) in toluene (100 ml.) and cyclohexanone (40 ml.) was distilled until 30 ml. of distillate had collected. Aluminium isopropoxide (2.5 g.) in toluene (10 ml.) was then added and the mixture refluxed for 1 hour. The cooled mixture was washed with dilute mineral acid, the solvents removed by steamdistillation, and the product isolated with ether. It was chromatographed on alumina (25 g.) employing benzene as eluent, when solid materials were obtained from the early fractions. These were purified from aqueous methanol to give flat needles of fi-methylprogesterone, M.P. 171 C., identical with a specimen prepared by method (a) above. 6fi-methylprogesterone (600 mg.) in methanol (25 ml.) was heated with potassium hydroxide (500 mg.) in water (5 ml.) under reflux in a stream of nitrogen for 16 hours. The product was isolated with ether and yielded 60: methylpregn-4-ene-3:20-dione (60c methylprogesterone) as flaky needles, M.P. 122 to 123 C., [a] +177 (c., 1.05 in chloroform), after crystallization from aqueous methanol.

We claim:

1. 6 8-methylandrost-4-ene-3z l7-dione.

2. a ethinyl 17,8 hydroxy 6/3 methylandrost- 4-ene-3-one.

3. 6B-methyl progesterone.

4. A method for the preparation of 6/3-methyl-3-oxo- A -steroids of the androstane and pregnane series which method comprises contacting with manganese dioxide :1 corresponding 3fi-hydroxy-6,B-methyl-A steroid to convert the 3,8-hydroxy group to a 3-keto group.

5. A method for the preparation of 6 3-methyl-3-0xo- A steroids of the androstane and pregnane series which method comprises contacting with a chromic oxidising agent a corresponding 3,3:5ot-dihydroxy-6fl-methyl steroid of the androstane and pregnane series to oxidize said steroid to a corresponding 5a-hydroxy-6e-methyl-3-oxo derivative and contacting the 5u-hydroxy-6B-methyl-3-oxo derivative with thionyl chloride in pyridine to remove the Sawhydroxy group and introduce a double bond at the A position.

6. A method as claimed in claim 5 wherein thionyl chloride in pyridine at 0 C. is employed 7. A method for the preparation of 6 8-methyl-3-oxo- A steroids of the androstane and pregnane series which 5 method comprises oxidising and dehydrating a corresponding 35:5a-dihydroxy-6B-methy1 steroid of the androstane and pregnane series in a single stage by contacting said corresponding steroid with an aluminum alkoxide in an organic solvent.

8. Sa-hydroxy-6 3-methy1allop1'egnane-3 :ZO-dione.

References Cited by the Examiner Campbell et al.: Iourn. Amer. Chem. Soc. (1958), vol. 80, pp. 4717-21.

6 David et a1.: Journ. Pharm. & Pharmosol. (1957), p. 929.

Madaeva et al.: Zhurnal Obshchei Khimei, vol. 10 (1940), No. 3, pp. 213-216.

Ringold et al.: Journal Organic Chemistry (1957), vol. 22, pp. 99-100.

LEWIS GOTTS, Primary Examiner.

L. H. GASTON, M. LIEBMAN, Examiners. 

1. 6B-METHYLANDROST-4-ENE-3:17-DIONE.
 3. 6B-METHYL PROGESTERONE. 